MDT (multi-disciplinary team) guidance for managing prostate cancer

MDT (Multi-disciplinary Team) 

Guidance for 

Managing Prostate Cancer 

Produced by: 

• British Uro-oncology Group (BUG) 

• British Association of Urological Surgeons (BAUS): Section of Oncology 

• British Prostate Group (BPG) 

This guidance has been supported by educational grants from Ferring Pharmaceuticals, 

Date of preparation: November 2009 GB.DOC.09.11.16 

2nd Edition (November 2009) 

Novartis and sanofi-aventis. The development and content of this guidance 

has not been influenced in any way by the supporting companies.

Abbreviations 

3D-CRT: three-dimensional conformal radiotherapy 

ADT: androgen deprivation therapy 

BPH: benign prostatic hyperplasia 

CAB: combined androgen blockade 

CHHiP: Conventional or Hypofractionated High Dose IMRT for Prostate Cancer 

CI: confidence interval 

CPA: cyproterone acetate 

CT: computed tomography 

DES: diethylstilbestrol 

DFS: disease-free survival 

DRE: digital rectal examination 

EBRT: external beam radiation therapy 

EPC: Early Prostate Cancer 

ERSPC: European Randomised Study of Screening for Prostate Cancer 

FFF: freedom from failure 

GnRH: gonadotrophin-releasing hormone 

HDR: high dose rate 

HIFU: high-intensity focused ultrasound 

HR: hazard ratio 

HRPC: hormone-refractory prostate cancer 

IMRT: intensity modulated radiotherapy 

IPSS: International Prostate Symptom Score 

LDR: low dose rate 

LHRH: luteinising hormone releasing hormone 

LTAD: long-term androgen deprivation 

MDT: multi-disciplinary team 

MRC: Medical Research Council 

MRI: magnetic resonance imaging 

MRS: magnetic resonance spectroscopy 

NCCN: National Comprehensive Cancer Network 

NICE: National Institute for Health and Clinical Excellence 

ONJ: osteonecrosis of the jaw 

OS: overall survival 

PFS: progression-free survival 

PLCO: Prostate, Lung, Colorectal and Ovarian 

ProtecT: Prostate Testing for Cancer and Treatment 

PSA: prostate-specific antigen 

RCT: randomised controlled trial 

SRE: skeletal-related events 

STAD: short-term androgen deprivation 

TRUS: transrectal ultrasound 

TURP: transurethral resection of the prostate 

2

Integrated Care and the Multi-disciplinary Team (MDT) 

• The concept of integrated care is becoming increasingly accepted as a way to overcome 

fragmentation of patient management and to provide a consistent treatment strategy across 

the MDT. It also creates an optimal structure that facilitates audit and peer review. 

• Integration within the MDT is essential for patients with prostate cancer because the 

collaboration between MDT members (Table 1) is central to the treatment strategy, with ongoing 

support from the wider team to manage pain and the adverse effects of therapy. By being familiar 

with the complete spectrum of management strategies, the MDT can assist patients in making 

treatment decisions that are specific for their individual disease state, co-morbid conditions, 

age and lifestyle. 

Table 1: The make-up of the MDT in the prostate cancer setting 

Urological surgeons Oncology and urology nurse specialists 

Clinical and medical oncologists (Palliative care specialist) 

MDT co-ordinator and secretarial support (Oncology pharmacists) 

Radiologists (Social workers) 

Histopathologists (Dieticians) 

• According to the UK-based Integrated Care Network, the move to true integrated practice can 

add value in the following ways: 1 

o Changing the identity or branding of a service to create more positive user responses and 

staff allegiances, enabling a clear break with the past. 

o Securing organisational efficiencies, for example, in the shape of shared support services, 

integrated management, innovative administrative processes and emerging hybrid roles. 

o Defining a focus for action that includes clearer processes of accountability and is less prone 

to distraction by wider organisational concerns. 

o Introducing more robust arrangements for team-working and leadership-working in 

challenging times. 

o Creating new opportunities for investment, for example, in IT systems, and opening access to 

new sources of funding. 

• The algorithms presented in this guidance provide a single framework that is adapted for each 

major category of prostate cancer: localised, locally advanced and advanced (Figure 1). 

• The treatment algorithms presented in this document (Figures 2−4) represent a management 

structure that goes beyond a simple co-ordinated system and will work most efficiently when 

the MDT is functioning as a single integrated unit. 

3

Figure 1: Summary of the definition of prostate cancer stages 

LOCALISED 

DISEASE 

T1/T2 

No/Mo 

Low Risk 

Gleason grade ≤6 

PSA ≤10 

Intermediate Risk 

Gleason grade 7 

and/or 

PSA (10-20) 

High Risk 

Gleason grade ≥8 

and/or 

PSA ≥20 

LOCALLY 

ADVANCED 

DISEASE 

(Non-metastatic) 

T1/T2 N+ Mo 

T3/T4 No/N+ Mo 

Failed local Rx 

with rising PSA 

and/or local 

recurrence+ Mo 

ADVANCED 

DISEASE 

(Metastatic) 

Proven M1 

4

Figure 2: Treatment algorithm for localised disease 

Key Questions for the MDT 

• TNM stage? 

• Gleason grade? 

• PSA/PSA Kinetics? 

• Age/co-morbidity/life 

expectancy? 

• Symptoms: 

– Bowel? 

– Urine IPSS score? 

• Sexual function? 

• Family history? 

Is this patient suitable for clinical trial? 

Low Risk 


PSA ≤10 

Active surveillance Radical prostatectomy 

Radical prostatectomy 

External beam radiotherapy 

(EBRT) +/– neo-adjuvant 

and concurrent hormone 

therapy 

Low dose rate (LDR) 

brachytherapy +/– neoadjuvant 

hormone therapy 

Watchful waiting 

Novel therapies 

MDT 

Diagnostic Tests 

• Digital rectal exam (DRE) 

• PSA 

• Transrectal ultrasound 

(TRUS)/biopsy 

• MRI/CT pelvic scan* 

• Bone scan* 

(*Not mandatory for low-risk patients) 

MANAGEMENT OPTIONS 



and/or PSA (10-20) 

EBRT +/– neo-adjuvant, 

concurrent or adjuvant 


LDR brachytherapy 

+/– EBRT 

+/– hormone therapy 



Ongoing Support 

Local patient support network 

Role of nurse/GP/healthcare professional team 

Key Discussion Points 

with the Patient 

• Survival/prognosis? 

• Treatment options? 

• Treatment side-effects? 

• Impact on quality of life? 

• Importance of: 

– Psychological impact 

to patient and family? 

– Family history? 

– Clinical trials? 

– Sexual function? 

– Urinary function? 

– Bowel function? 

– Physical strength, energy? 

– Level of activity? 

– Accessibility to Rx? 

High Risk 


and/or PSA ≥20 

Selected Selected 

For treatment 

approach see 

locally advanced 

management 

5

Figure 3: Treatment algorithm for locally advanced (non-metastatic) disease 






expectancy? 

• Symptoms: 

– Bowel? 




• Bone pain? 

• Osteoporosis risk? 


High-risk localised 




• PSA 


(TRUS)/biopsy 

• MRI/CT pelvic scan 

• Bone scan 

• Consider lymph node sampling 

(if this will determine changes 

in management approach) 

MANAGEMENT OPTIONS 1 

T1/T2 N+ Mo 


External beam radiotherapy (EBRT) 

+/- HDR brachytherapy boost 

+/-neo-adjuvant, concomitant 

and adjuvant hormone therapy 

Hormone therapy alone 






















6

Figure 3: Treatment algorithm for locally advanced (non-metastatic) disease (cont.) 


Post-radical prostatectomy 


Failed local Rx with rising PSA 

and/or local recurrence+ Mo 

Active surveillance/watchful waiting Active surveillance/watchful waiting 

Hormone therapy alone Hormone therapy alone 


(EBRT) +/– concomitant +/– 

adjuvant hormone therapy 

Post-radical radiotherapy/ 

brachytherapy 

Salvage prostatectomy 

Novel local salvage therapy 




7

Figure 4: Treatment algorithm for advanced (metastatic) disease 






expectancy? 

• Symptoms: 

– Bowel? 






• Palliative care referral? 


Palliative Care 

• Pain control 

• Local radiotherapy 

Bone pain 

Spinal cord compression 

Nerve root compression 

• Continual assessment 

Second-/third-line if 

androgen sensitive? 




• PSA 

• Transrectal ultrasound (TRUS)/ 

biopsy (non mandatory if PSA 

>100 and radiological evidence 

of metastases) 

• Biochemistry screen 

• Full blood count 

• Bone scan 



Proven M1/M2 

First line hormone therapy 

Significant rise in PSA Clinical/ 

radiological progression 

Observation 

Second-/third-line hormone 

therapy 

Further progression 





















HRPC 

Clinical trials 

Chemotherapy 

Strontium 

Bisphosphonate 

8

Integrated care and clinical governance 

• The effective functioning of the MDT and tailored care pathways for patients will support the 

(now routine) clinical governance procedures implemented throughout the NHS. Traditionally, 

clinical governance relates to a single organisation or service and this can raise challenges, with 

the recognition that patients require management across different organisations and services. 

Therefore, it is appropriate to apply the principles of clinical governance to individual patients or 

groups of patients. 

• The focus should be on optimum patient satisfaction and care, rather than on performance of 

the NHS institution. The MDT and development of organised pathways (allowing for individual 

clinical discretion and patient involvement in decision-making) ensures that the patient’s journey 

is monitored and assessed as a single entity. 

9

Approach within the MDT 

Key questions for the MDT 



• Prostate-specific antigen (PSA) concentration? 

• Risk group (according to National Comprehensive Cancer Network [NCCN] guidelines)? 

• Age/co-morbidity/life expectancy? 

• Symptoms: 

o International Prostate Symptom Score (IPSS), bowel, urinary? 





• Clinical trials? 

• The MDT is an essential part of cancer management. However, there are often difficulties in 

knowing which patients to discuss, ensuring that their details and diagnoses are available, 

and keeping a record of decisions made at the meetings. 

• MDTs have repeatedly been endorsed as the principal mechanism for ensuring that all relevant 

disciplines and professional groups contribute to, and participate in, decisions regarding the 

clinical management of patients. 2 

• MDT-working is positively related to a range of measures of effectiveness, including the quality 

of clinical care. 

• It is important to emphasise the distinction between management and administration. 

• A central concept of integrated care is to reinforce the role of the MDT (working as a single unit), 

but with enough clinical freedom to tailor management strategies to the needs of individual 

patients. 

• Treatment strategies are influenced by the stage of disease and by an interaction between 

the risk of disease progression, survival and key patient characteristics, such as age, lifestyle 

and general health. The discussion of these factors is of crucial importance in determining the 

most appropriate way forward. For example, age and the presence of co-morbidities may be a 

restrictive factor when considering surgery. 

• The case notes, pathology reports, test results and radiology for each patient must be available 

to be discussed at the meeting. The MDT must also ensure that the patient has the fullest possible 

role in determining treatment − the importance of this cannot be overstated. Patient preference 

should be discussed within the MDT. Although the majority of men with prostate cancer want to 

be involved in treatment decisions, an estimated one in five of all patients does not raise, or really 

understand, the potential issues and associated side-effects of treatments and alternatives that 

may be available to them. 3 

• The possibility of including a patient in a relevant clinical trial should not be forgotten. 

10

Approach to the Patient 

Key points for discussion with the patient 

• Survival prognosis? 





o Sexual function? 

o Urinary function? 

o Bowel function? 

o Physical strength, energy? 

o Level of activity? 

o Accessibility to prescribed drugs? 

o Psychosocial impact on them and their family? 


• Clinical trials? 

The patient’s expectations 

The patient should have the right to discuss their treatment with 

appropriately trained members of the MDT 

• After a diagnosis of prostate cancer, most men will want to have some involvement in the 

decisions concerning their care. The following aspects have been found to be important: 4 

o Honesty about the severity of the cancer and their prognosis 

o Discussion of the best treatment options 

o The clinician being up-to-date on ongoing and recent research 

o Disclosing all treatment options 

o How cancer may affect their daily functioning 

• It is essential that the patient and healthcare professionals discuss the likelihood of adverse 

events associated with each treatment option and implications for their future lifestyle when 

determining management strategies. 

• The patient and his partner, family and/or other carers should be fully informed about care and 

treatment options and therefore able to make appropriate decisions based upon the choices 

offered by their healthcare professionals. For example, the choice between radical treatment and 

active surveillance may be influenced by a patient’s desire to retain sexual activity, physical energy 

and quality of life. 

• Patients should be informed and advised regarding the available treatment options and the 

potential effects of these on their lifestyle and quality of life. 

11

Discussing evidence with patients 

There is a lack of evidence to guide how healthcare professionals can most effectively share clinical 

data with those patients facing treatment decisions. However, basing recommendations largely on 

relevant clinical studies and expert opinion, it is possible to achieve five communication objectives 

when framing and communicating clinical evidence. 

1. Understand the patient’s experience, expectations and preferences 

2. Build partnerships with the patient and carer 

3. Provide evidence and discuss uncertainties and side-effects 

4. Present recommendations 

5. Check for understanding and agreement 

12

Assessment and Diagnosis 

Screening 

• PSA screening remains a relatively contentious subject in the field of prostate cancer. It is felt that 

robust evidence is lacking concerning whether screening results in a reduction in mortality from 

the disease. 

• Three ongoing large, randomised, controlled clinical trials are evaluating the value of PSA 

screening for prostate cancer: the European Randomised Study of Screening for Prostate Cancer 

(ERSPC), 5 the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial in the US6 

and the UK-based Prostate Testing for Cancer and Treatment (ProtecT) study. 7 The first reports 

from these trials have been published and have added further information to the PSA screening 

debate: 

o The PLCO study reported no mortality benefit with the combination of PSA screening and 

digital rectal examination (DRE) during a median follow-up of 7 years. 6 

o In contrast, the ERSPC trial found that PSA screening was associated with a 20% relative 

reduction in prostate cancer mortality at a median follow-up of 9 years, equivalent to the 

prevention of approximately 7 prostate cancer deaths per 10,000 men screened. This mortality 

benefit was associated with a high risk of overdiagnosis, with nearly 76% of men who 

underwent a biopsy following an elevated PSA value having a false positive result. 5 

o ProtecT has demonstrated a benefit of repeat PSA testing in reducing the risk of high-grade 

prostate cancer in men with an initial PSA concentration of 3−20 ng/ml. 7 

• Quality of life and cost-effectiveness analyses from the ERSPC and PLCO trials, along with 

mortality results from ProtecT are needed to help resolve the ongoing PSA screening debate. 

Risk factors for prostate cancer 

The risk factors for prostate cancer are generally well-documented, but are highlighted here for 

completeness of the Guidance. 

• Age 

o Relatively rare in men under the age of 50 years. 

o Incidence increases in those over 60 years. 

• Race 

o A higher incidence of the disease is seen in African-Caribbean, African-American and West 

African races. The UK PROCESS study is compiling equivalent UK data. 8 

o Men of Chinese and Japanese origin have a low incidence of disease. 

• Geography 

o The highest incidence of prostate cancer is currently seen in North America and 

Northern Europe. 

• Family history 

o Men with a first-degree relative affected by prostate cancer have a relative risk of 

developing the disease themselves 2-fold greater than men with no relatives affected. 9 

o Those men with an affected second-degree relative have an increased relative risk 

of 1.7 of developing the disease. 

o Men with both a first- and second-degree relative affected have an increased relative 

risk of 8.8 of developing the disease. 

13

o There is also some evidence to show a link between an increased risk of prostate cancer 

where there is a family history of breast, ovarian, bladder or kidney cancer. 10 

o The UK Familial Prostate Cancer Study is currently looking at the genetics of the disease 

with possible sites of interest lying on chromosomes 2, 5, Y and loss of heterozygosity at 

10q and 16q. 

Diagnostic tests 

DRE 

• The DRE remains valid as an initial method for assessing the prostate; however, DRE findings 

should not be regarded as a fail-safe test. 

PSA 

• As an independent variable, PSA concentrations are a better predictor of cancer than suspicious 

11, 12 

findings on DRE or transrectal ultrasound (TRUS). 

• Serum concentrations of PSA can be elevated in the presence of benign prostatic hyperplasia 

(BPH), prostatitis and other non-malignant conditions. Furthermore, there is, as yet, no 

recommendation for the optimal PSA threshold value that most effectively avoids the detection 

13, 14 

of insignificant cancers that are unlikely to be life-threatening. 

• While PSA concentrations generally increase with advancing disease stage, the ability of PSA levels 

to accurately predict pathological stage in any one individual is low. 15−17 

• Asymptomatic patients who request a PSA test should be counselled before the procedure 

for the following reasons: 18 

o Although the test may detect a cancer at a stage where curative treatment can be offered, 

PSA will fail to detect some early tumours. 

o A PSA test may detect early prostate cancer in an estimated 5% of men aged 50−65 years. 

o Treatment of early prostate cancer can put the patient at some risk and may not necessarily 

improve life expectancy. 

Factors affecting PSA concentrations are summarised below. 

Age and race 

Table 2: Age-specific PSA (ng/ml) reference ranges, by race 19 

Age (years) White Black Latino Asian 

40−49 0−2.3 0−2.7 0−2.1 0−2.0 

50−59 0−3.8 0−4.4 0−4.3 0−4.5 

60−69 0−5.6 0−6.7 0−6.0 0−5.5 

70−79 0−6.9 0−7.7 0−6.6 0−6.8 

Biopsy/transurethral resection of the prostate (TURP) can cause an increase in PSA for a variable time 

period (4−12 weeks). 20 

Prostatitis can cause an increase in PSA concentration, which can be reduced to within a normal range 

21, 22 

with antibiotic treatment. 

14

Prostate size – a benignly enlarged gland can influence PSA concentrations. 

Infection – elevated PSA levels can be seen beyond 6 months in up to 50% of patients when associated 

with febrile urinary tract infections. 

Free and complexed PSA should be understood. Catalona et al. conclude that percentage free PSA 

is most useful in men with a PSA concentration in the range 2−15 ng/ml (Table 3); the higher the 

percentage of free PSA the lower the probability of cancer. 23 

Table 3: Probability of prostate cancer based on total and percentage free PSA 23 

Total PSA (ng/ml) 

PSA density i.e. PSA level (ng/ml) 

TRUS-determined prostate volume (ml) 

Probability of cancer (%) 

0−2 ~1 

2−4 15 

4−10 25 

>10 >50 

Free PSA (%) 

0−10 56 

10−15 28 

15−20 20 

20−25 16 

>25 8 

May be helpful in differentiating BPH from prostate cancer in patients who have a normal DRE with 

a PSA 4−10ng/ml. A PSA density >0.15 may suggest prostate cancer. 

PSA velocity can be valuable in the follow-up of men with a normal PSA but prior negative biopsies. 

Velocity is measured by a change in PSA concentration in three consecutive measurements taken at 

6-monthly intervals. A change in PSA concentration of >0.75 ng/ml per year is more likely to indicate 

prostate cancer than BPH. The usefulness of PSA velocity in those with a PSA concentration >10 ng/ml 

is unknown. 24 

TRUS 

• TRUS detects 50% more patients with prostate cancer than physical examination alone, 25, 26 but 

the ultrasonic appearance of prostate cancer is variable and only a very small number of cancers 

are detected if a DRE and PSA test are normal. 26−28 Therefore, TRUS is mainly used to aid biopsy. 

15

Biopsy and tumour grading 

• The National Institute for Health and Clinical Excellence (NICE) prostate cancer guideline 

recommends that the serum PSA level alone should not automatically lead to a prostate biopsy. 29 

It states that to help men decide whether to have a prostate biopsy, healthcare professionals 

should discuss with them their PSA level, DRE findings (including an estimate of prostate size) 

and co-morbidities, together with their risk factors (including increasing age and black African 

and black Caribbean ethnicity) and any history of a previous negative prostate biopsy. 

• NICE further highlights that men and their partners or carers should be given information, 

support and adequate time to decide whether or not they wish to undergo prostate biopsy. 29 

Men will need to comprehend the potential risks (such as potentially living with a diagnosis of 

prostate cancer that is deemed clinically insignificant) and the benefits of prostate biopsy. 

• Where biopsy is indicated, a minimum of 10 biopsies should be obtained, according to the volume 

of the prostate. Biopsies should be performed under local anaesthetic and antibiotic cover. 30 

• A European study has reported that a prostate cancer detection rate for the first set of biopsies 

is 24% and for the second set of biopsies after a negative initial set as 13%. 31 

Magnetic Resonance Imaging (MRI) 

• The classification used for staging prostate cancer is the internationally approved system 

recommended by the Union International Contra Cancer (available at: www.uicc.org). 

• TNM staging, Gleason score, and PSA concentration facilitate estimation of the risk of 

extracapsular disease and lymph node metastases. Pelvic staging is required for those of high 

or intermediate risk (according to NCCN classification). MRI is the preferred option to stage pelvic 

lesions and where MRI is contraindicated, computed tomography (CT) should be used. 29 

• Body coil MRI is sensitive and specific in identifying extracapsular extension of prostate cancer 

in patients with high- or intermediate-risk disease. 32 

• NICE concludes: 29 

o MRI is now the most accurate and commonly-used imaging technique for tumour-staging 

men with prostate cancer. Many of the original publications used now outdated MRI 

technology, and the accuracy reported for MRI is improving, typically with endorectal coil 

imaging at 1.5 Tesla. 

o After transrectal prostate biopsy, intra-prostatic haematoma can affect image interpretation 

for at least 4 weeks. 

o Magnetic resonance spectroscopy (MRS) is an experimental technique based on the 

concentration of metabolites such as choline and citrate in the prostate gland. Prostate cancer 

alters the concentrations of these metabolites and this may be used to find areas of tumour 

activity. MRS is not recommended for men with prostate cancer except in the context of a 

clinical trial. 

Bone scans and lymph node sampling 

• Bone scans (particularly in patients with PSA concentration >20 ng/ml) and lymph node biopsies 

are also important in the assessment process. A PSA concentration of






expectancy? 

• Symptoms: 

– Bowel? 





Localised Disease: Management Options 

Figure 2: Treatment algorithm for localised disease 

Low Risk 


PSA ≤10 

Active surveillance Radical prostatectomy 



(EBRT) +/– neo-adjuvant 

and concurrent hormone 

therapy 

Low dose rate (LDR) 

brachytherapy +/– neoadjuvant 







• PSA 


(TRUS)/biopsy 

• MRI/CT pelvic scan* 

• Bone scan* 

(*Not mandatory for low-risk patients) 




and/or PSA (10-20) 

EBRT +/– neo-adjuvant, 

concurrent or adjuvant 


LDR brachytherapy 

+/– EBRT 

+/– hormone therapy 























High Risk 


and/or PSA ≥20 

Selected Selected 

For treatment 

approach see 

locally advanced 

management 

17

The following guidance for managing localised prostate cancer focuses on low- and intermediate-risk 

categories, defined here as: 34 

• Low risk (T1c/T2a; Gleason grade ≤6; PSA concentration ≤10 ng/ml) 

• Intermediate risk (T2b; Gleason grade 7 and/or PSA concentration: >10 and ≤20 ng/ml) 

In the proposed management algorithms, high-risk localised disease falls more naturally into 

management of locally advanced disease. 

Patient choice and the presence or absence of co-morbidities should be an essential component 

of management decisions in men with localised disease. Decisions concerning the choice of radical 

treatments need to be carefully balanced with the different options available and the impact of such 

treatments on a patient’s co-morbidities. 

In this section available evidence for the following management approaches is outlined: 

• Active surveillance 

• Watchful waiting 

• Radical prostatectomy 

• External Beam Radiation Therapy (EBRT) 

• Low dose rate brachytherapy 

• Neoadjuvant/adjuvant hormone therapy 

• Novel therapies 

There is no consistent evidence for superiority of any of the three main radical treatments: radical 

prostatectomy, EBRT or brachytherapy. 

18

Active surveillance 

Overview 

• Active surveillance is an approach to the management of early prostate cancer in which the choice 

between curative treatment and observation is based on evidence of disease progression (PSA 

kinetics or repeat biopsy findings) during a period of close monitoring. The aim is to reduce the 

burden of treatment side-effects without compromising survival. 

• Patients suitable for active surveillance are those with low-risk localised disease who are fit for 

radical treatment. Ongoing prospective studies of active surveillance have shown that 60−80% 

of such men will avoid the need for treatment, and that 100% prostate cancer-specific survival 

35, 36 

at 10 years is achievable. 

• Active surveillance should be distinguished from watchful waiting. Traditional watchful waiting 

involves relatively lax observation with late, palliative treatment for those who develop symptoms 

of progressive disease. In contrast, active surveillance involves close monitoring with early, radical 

treatment in those with signs of disease progression. 

Patient selection 

• Low-risk, clinically localised prostate cancer 

o Clinical stage T1c/2a 

o Gleason grade ≤3+4 

o PSA concentration

• Van As et al. reported the outcome of 326 men recruited to the Royal Marsden active surveillance 

study from 2002 to 2006, at a median follow-up of 22 months. 35 Median age was 67 years, 

and median initial PSA concentration 6.4 ng/ml. Sixty-five patients (20%) had deferred radical 

treatment, 16 (5%) changed to watchful waiting because of increasing co-morbidity, 7 (2%) died 

of other causes, and 238 (73%) remain on surveillance. There were no deaths from prostate cancer 

and no men had developed metastatic disease. 

• It is possible that targeted radical treatment, based on an active surveillance strategy, will be as 

effective, and considerably less morbid, than radical treatment for all cases. The ProSTART phase III 

trial will compare the long term outcomes of active surveillance with those of immediate radical 

treatment, and aims to recruit approximately 2100 patients. 

20


Overview 

• Watchful waiting is an approach to the management of localised prostate cancer that aims to 

avoid treatment, or delay it for as long as possible. Patients who eventually develop symptoms 

of progressive prostate cancer receive palliative treatment, usually with hormone therapy. 

• Watchful waiting is particularly suitable for patients aged over 75 years or younger men with 

significant co-morbidities. 

• Watchful waiting should be distinguished from active surveillance. Conventional watchful waiting 

involves relatively lax observation with late, palliative treatment for those who develop symptoms 

of progressive disease. In contrast, active surveillance involves close monitoring with early, radical 

treatment in those with signs of progression. 


• Asymptomatic clinically localised prostate cancer 

o Clinical stage T1−3 

o Gleason score ≤7 

o Any PSA concentration 

o Not suitable for radical treatment (usually by virtue of older age or co-morbidities) 

Side-effects 

• Uncertainty 

Clinical evidence 

• The NICE clinical guideline confirms a lack of evidence for watchful waiting and the Guideline 

Development Group reached a consensus that the recommendation from NICE would avoid 

unnecessary investigations: 29 

o Men with localised prostate cancer who have chosen a watchful waiting regimen and who 

have evidence of significant disease progression (that is, rapidly rising PSA level or bone pain) 

should be reviewed by a member of the urological cancer MDT. 

21

Radical treatments 


There are now four approaches to performing a radical prostatectomy: retropubic, perineal, laparoscopic 

and robotic. The procedure involves removal of the whole prostate and the seminal vesicles. The most 

commonly used approaches are retropubic and perineal, but laparoscopic and robotic techniques are 

becoming more frequently adopted. The newer approaches have the advantage of reduced blood loss 

and shorter inpatient stays. 

Overview 

• In 1997, Selley et al. reviewed a total of 17 studies (two randomised controlled trials [RCTs] and 

15 observational studies involving a total of 5410 patients) to investigate the efficacy of radical 

prostatectomy for men with localised prostate cancer. Cancer-specific survival after 10 years of followup 

ranged from 86% to 91%, with clinical disease-free survival (DFS) ranging from 57% to 83%. 38 


• Anaesthetic fitness 

• At least 10 years’ life expectancy 

• Complications increase and benefits decrease in patients aged >70 years 

Side-effects of treatment 

• Based on the systematic review by Selley et al., the following side-effects should be considered: 38 

o Operative and post-operative mortality: 0.2−1.2% 

o Sexual dysfunction: 51−61% 

o Incontinence (mild stress): 4−21% 

o Incontinence (total): 0−7% 


• One randomised trial has compared radical prostatectomy with watchful waiting in localised 

prostate cancer. 39 

o The trial randomised 695 men with localised disease between radical prostatectomy and 

watchful waiting. 

o At a median follow-up of 8.2 years, randomisation to radical prostatectomy was associated with 

a benefit both in terms of disease-specific mortality (hazard ratio [HR] 0.56; 95% confidence 

interval [CI]: 0.36−0.88; p=0.01) and overall mortality (HR 0.74; 95%CI: 0.56−0.99; p=0.04). 

o This translated into 10-year OS of 73% versus 68% (p=0.04) for radical prostatectomy versus 

watchful waiting. 

o In terms of 10-year freedom from distant metastases, the absolute benefit of surgery versus 

watchful waiting was 10% (84.8% versus 74.6%; p=0.004). 

o However, patients need to weigh these benefits against the risk of adverse consequences of 

treatment. The 5% absolute improvement in 10-year survival was achieved at the expense of a 

35% absolute increase in the risk of erectile dysfunction and a 28% absolute increase in the risk 

of urinary leakage. 

22

o Faced with these figures, some patients would choose surgery, but many would choose 

conservative management. 40 

• The above findings are now updated to incorporate a further 3 years of follow up. At 12 years: 41 

o 12.5% of the surgery group and 17.9% of the watchful waiting group had died of prostate 

cancer (difference = 5.4%, 95%CI: 0.2−11.1). 

o 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been 

diagnosed with distant metastases (difference = 6.7%, 95%CI: 0.2−13.2). 

o This follow-up analysis was consistent with the previous findings. Radical prostatectomy can 

reduce prostate cancer mortality and risk of metastases but no further benefits were seen 

beyond 10 years of follow up in this study. 

Neoadjuvant and adjuvant hormone therapy with radical prostatectomy 

• At present, evidence suggests that the down-staging achieved with neoadjuvant hormone 

therapy does not translate into improved DFS, and therefore cannot be recommended outside 

of clinical trials. 42−45 

• Similarly, there is currently no evidence that adjuvant hormone therapy provides a survival 

46, 47 

advantage for patients with pathologically proven localised disease. 

Adjuvant radiotherapy after radical prostatectomy 

• The EORTC 22911 study was designed to investigate benefit for immediate postoperative 

radiotherapy in 502 patients with pT3 disease or positive surgical margins as opposed to 

radiotherapy offered for biochemical or clinical relapse. 48 

o After a median follow up of 5 years, biochemical progression-free survival (PFS) was 

significantly improved in the immediate radiotherapy group (74.0% versus 52.6%; 

p

External Beam Radiotherapy (EBRT) 

Overview 

• Selley et al. reviewed 21 observational studies and one RCT involving radiotherapy and found that 

survival and recurrence rates are associated with grade and stage of the disease. The 5-year DFS 

for those with T1–T2 stage disease averaged 70−80%. Local progression was observed in 10−20% 

of these patients, while distant metastases were observed in 20−40%. 38 

• Nilsson et al. performed a systematic overview of radiotherapy in prostate cancer. Data from 26 

non-randomised trials of conventional EBRT showed a 10-year DFS of 100%, 69% and 57% for 

T1a, T1b and T2 stage disease, respectively. 51 

• Long-term follow-up after EBRT continues to demonstrate an improvement in cause-specific 

survival. Improved selection and technical developments in radiotherapy leading to increased 

doses have shown better results. 

Three-dimensional conformal radiotherapy (3D-CRT) 

• There is evidence that increased radiation dose is associated with increased cancer cell kill for men 

with localised prostate cancer. However, the traditional two-dimensional technique of treatment 

planning and delivery is limited by the normal tissue toxicity of the surrounding structures 

(bladder, rectum and bowel), such that the dose that can be safely delivered to the prostate 

by EBRT is 65−70 Gy. Several technological advances over the last 20 years have enhanced the 

precision of EBRT, and have resulted in improved outcomes. 

• The three-dimensional conformal radiotherapy (3D-CRT) approach reduces the dose-limiting late 

side-effect of proctitis 52 and has allowed for dose escalation to the whole prostate to 78 Gy. 

Intensity Modulated Radiotherapy (IMRT) 

• IMRT is an advanced technique of 3D-CRT. IMRT can modify the shape and intensity of the 

multiple radiotherapy beams. It is very precise in targeting the treatment area, sparing 

surrounding tissue. IMRT is currently under evaluation, particularly for the irradiation of pelvic 

lymph nodes. 

• IMRT may result in reduced rectal toxicity when using doses greater than 80 Gy. 

Dose escalation 

• Evidence of the benefits of dose escalation has been demonstrated for T1−T3 prostate cancer by 

Pollack et al. in a phase III randomised study undertaken at the MD Anderson Hospital. 53 

o A total of 305 men were randomised between 1993 and 1998 to compare the efficacy of 70 

Gy versus 78 Gy with a median follow-up of 60 months. The primary endpoint was freedom 

from failure (FFF), including biochemical failure, which was defined as three rises in PSA level. 

o The FFF rates for the 70 Gy and 78 Gy arms at 6 years were 64% and 70%, respectively (p=0.03). 

Dose escalation to 78 Gy preferentially benefited those with a pre-treatment PSA concentration 

>10 ng/ml; the FFF rate was 62% for the 78 Gy arm versus 43% for those who received 70 Gy 

(p=0.01). For patients with a pre-treatment PSA concentration ≤10 ng/ml, no significant doseresponse 

relationship was found, with an average 6-year FFF rate of about 75%. 

o Although no difference in OS occurred, the freedom from distant metastasis rate was 

higher for those with PSA levels >10 ng/ml who were treated to 78 Gy (98% versus 88% 

at 6 years, p=0.056). 

24

• Dearnaley and colleagues have reported their findings from the MRC RT01 study. 54 

o In this 3D-CRT trial, 843 men were randomised to a standard dose of 64 Gy compared with 

an escalated dose of 74 Gy, with all men also receiving neoadjuvant hormone therapy. 

o Patients receiving the conventional dose had 5-year biochemical PFS rates of 60% compared 

to 71% in the dose-escalated arm. Advantages were also seen in terms of clinical PFS and the 

decreased use of androgen suppression. 

o Although these and other studies have shown benefits from dose escalation with 3D-CRT 

techniques, this has been offset to a degree by a reported increase in late rectal toxicity. 

• Prospective non-randomised studies conducted at the Memorial Sloan Kettering cancer centre 

have compared the outcomes of 1100 men who received doses in the range of 64−70 Gy and 

76−86 Gy using IMRT. 55 

o The results were evaluated within prognostic risk groups (using clinical stage, Gleason grade 

and presenting PSA concentration). They demonstrated that increasing the dose delivered 

beyond 70.2 Gy in men with intermediate- and high-risk disease improved the 5-year actuarial 

PSA relapse-free survival rate from 50% to 70% and 21% to 47%, respectively, in these two 

risk categories. 

• IMRT has the potential to reduce late rectal toxicity as shown in a further study that reports 3-year 

actuarial ≥grade 2 gastrointestinal toxicity at 4%. 56 

• A further development under investigation involves a change in the traditional fractionation 

schedules. Hypofractionation may improve cancer control for the same level of radiation-related 

toxicity and be a more effective treatment for prostate cancer with a predicted low alpha/ 

beta ratio. Phase II dose escalation studies using shortened schedules of hypofractionated IMRT 

regimens have indicated acceptable early toxicity. 57 

• The CHHiP (Conventional or Hypofractionated High Dose IMRT for Prostate Cancer) study is 

currently recruiting patients in the UK to compare standard fractionation IMRT (74 Gy in 37 

fractions) to two hypofractionated IMRT regimens (60 Gy in 20 fractions or 57 Gy in 19 fractions) 

in combination with neoadjuvant hormone therapy. 58 


• EBRT can be unsuitable for patients with bilateral hip replacement, previous radiotherapy, severe 

proctitis or bowel morbidity. 

Side-effects 

• Acute complications include cystitis, faecal frequency and urgency, proctitis and rectal bleeding. 

• Late complications occurring 3 months or later after treatment include impotence, bleeding, 

proctitis and diarrhoea. 

EBRT plus neoadjuvant hormone therapy 

• Neoadjuvant hormone therapy reduces prostate volume by 30−40%. 59, 60 This can reduce the size of 

the treatment field and as a result the level of toxicity experienced. 

• There are also reports of an additive or synergistic effect on tumour cell kill with combined 

therapy. Theories as to the mechanism of this include improved oxygenation by reducing tumour 

bulk and movement of hormone-responsive cells into a resting phase, which could reduce 

repopulation rate and enhance tumour cell death (increased apoptosis). 61 

• The RTOG 86-10 trial randomised 471 men with T2−T4 prostate cancer to radiotherapy +/− 4 

months of androgen deprivation therapy (ADT) before and during EBRT or to radiotherapy alone. 62 

25

o At median follow-up of 8.7 years, there was a trend to improved survival (8-year survival 

53% versus 44%, p=0.1) for those treated by hormone therapy with radiotherapy, which was 

significant for the subgroup with Gleason grade 2−6 disease (70% versus 52%, p=0.015). 62 

o Ten-year OS estimates (43% versus 34%) and median survival times (8.7 versus 7.3 years) 

favoured combined therapy with hormones and radiation compared to radiation treatment 

alone; however, these differences did not reach statistical significance (p=0.12). 

o There was a statistically significant improvement in 10-year disease-specific mortality 

(23% versus 36%; p=0.01), distant metastases (35% versus 47%; p=0.006), DFS (11% versus 

3%; p

Low dose rate (LDR) brachytherapy 

Overview 

• In 2005, NICE reviewed the medical literature on LDR brachytherapy and concluded that, in the 

absence of randomised trials, the results of LDR brachytherapy are comparable to those achieved 

with surgery or EBRT in well-selected patients. 66 

• Suitable patients include those with localised disease (up to T2a) with a Gleason grade ≤6, and a 

PSA concentration ≤10 ng/ml. Patients with significant urinary symptoms or post-TURP may not be 

suitable. 

• Brachytherapy is as effective as radical prostatectomy in patients with low-risk localised disease. 67 

• In intermediate-risk localised disease, the comparison is less clear, because many studies have 

added EBRT in combination. 68 

• Brachytherapy is a single-step procedure following a spinal or general anaesthetic. 

Brachytherapy plus EBRT 

• In a matched-pair analysis, the 5-year biochemical failure-free survival rate was 86% for patients 

treated with EBRT and LDR brachytherapy, and 72% for patients treated with EBRT alone (p=0.03). 

Both treatments were associated with comparable incidences of late genitourinary side-effects 

(18−19%). Late rectal toxicity decreased by 15% in patients treated with EBRT and brachytherapy 

(p=0.0003). 69 

Brachytherapy plus neoadjuvant hormone therapy 

• The role of neoadjuvant hormone therapy with brachytherapy is controversial. It is used to 

reduce the prostate volume when it exceeds 50 ml, in order to facilitate brachytherapy. Volume 

reduction decreases the total isotope activity required, potentially improves implant dosimetry 

and decreases pubic arch interference. 70 

Patient selection (exclusions) 

• Prostate size >50 ml 

• Recent TURP 

• Significant urinary outflow obstruction 

• Previous AP resection 

• Previous high dose pelvic radiotherapy 

27

Side-effects 

• A review of 16 studies by Crook et al. showed acute adverse events as: 67 

o Irritant urinary symptoms: 46−54% 

o Acute urinary retention: 1−14% 

o Acute proctitis: 1−2% 

o Chronic adverse events (reinforced by Wills et al., 1999 71 ): 

• Incontinence: 5−6% 

• Haematuria: 1−2% 

• Strictures: 1−2% 

• Proctitis: 1−3% 

• Erectile dysfunction: 4−14% (or up to 38% in Wills et al., 1999 71 and up to 50% at 5 years 

in Merrick et al., 2001 68 ). 


Table 4: Experience using trans-perineal implants as monotherapy (T1, T2 cancers) 

Author Number of men Isotope 

*Series excluded Gleason grade >7, 38% with pre-treatment PSA ≤4.0 ng/ml 

Median follow-up PSA results 

(months) (months) 

Beyer & Priestley, 

79% with PSA 

489 I-125 35 

199772


Cryotherapy/High-intensity focused ultrasonography (HIFU) 

• The development of third-generation prostate cryotherapy has allowed the introduction of 

ultra-thin needles to deliver a minimally-invasive treatment for prostate cancer patients in the 

primary and salvage setting 

79, 80 

o Early results established the low incidence of serious side-effects and good PSA control 

o Longer-term follow-up series show biochemical DFS at 10 years of 80.56% for low-risk, 

74.16% for moderate-risk and 45.54% for high-risk prostate cancer patients 

• This treatment has been approved by the American Urological Association and the European 

Association of Urology for treatment of patients with primary and radiation-failed prostate 

cancer 

• In the NICE guidelines, the minimally-invasive treatments of cryosurgery and HIFU were 

considered to be experimental and for use only within the clinical trial setting 29 

o After further clarification, it was agreed that these treatments would be funded by Primary 

Care Trusts provided patient data were collected in an approved way. Following consultation 

with the BAUS section of Oncology, a national database has been established to collect data 

from prostate cancer patients undergoing cryotherapy or HIFU for prostate cancer. Inclusion 

of patients in this database is considered necessary to fulfil the NICE guidelines. 

• These treatments may be offered to patients with stage T1, T2 or T3 as a primary treatment or in 

salvage prostate cancer patients. 

o The staging requirements are a positive biopsy and MRI and bone scan showing no evidence 

of metastatic spread. 

29

Locally Advanced Disease (Non-metastatic): 

Management Options 

Figure 3: Treatment algorithm for locally advanced (non-metastatic) disease 






expectancy? 

• Symptoms: 

– Bowel? 







High-risk localised 




• PSA 


(TRUS)/biopsy 


• Bone scan 

• Consider lymph node sampling 

(if this will determine changes 

in management approach) 


T1/T2 N+ Mo 


External beam radiotherapy (EBRT) 

+/- HDR brachytherapy boost 

+/-neo-adjuvant, concomitant 

and adjuvant hormone therapy 

Hormone therapy alone 






















30

The term locally advanced prostate cancer can be used to encompass a spectrum of disease profiles 

that may include any of the following: 

• Clinical stage T3, T4 or N1 cancers without evidence of distant metastases (M0) 

• Clinical stages T1 and T2 (‘localised’) at diagnosis, where ‘high-risk’ features (PSA concentration 

≥20 ng/ml or Gleason grade ≥8) indicate the likelihood of extraprostatic invasion or clinically 

undetectable metastatic disease 

• Pathological stage pT2 or pT3 disease with ‘high-risk’ features due to upstaging from additional 

pathological information after radical prostatectomy 

Men with locally advanced or high-risk prostate cancer generally have a significant risk of disease 

progression and cancer-related death if left untreated. These patients present two specific challenges. 

There is a need for local control and also a need to treat any microscopic metastases likely to be 

present but undetectable until disease progression. The optimal treatment approach will often 

therefore utilise multiple modalities. The exact combinations, timing and intensity of treatment 

continue to be strongly debated. Management decisions should be made after all treatments have 

been discussed by the MDT and the balance of benefits and side-effects of each therapy modality have 

been considered by the patient with regard to their own individual circumstances. 


Overview 

• Data on the use of watchful waiting in locally advanced disease is sparse. 

• Two non-randomised studies concluded that immediate orchidectomy was not associated with a 

81, 82 

survival advantage compared with therapy delayed until metastatic progression. 

• A pooled analysis of data from 2 RCTs involving 1036 men with locally advanced disease not 

suitable for curative treatment (T2−T4) suggested no survival benefit for immediate versus 

delayed hormone therapy at 1, 5 or 10 years. 83 


• Adolfsson et al. prospectively followed 50 patients with locally advanced prostate cancer who 

were only treated upon patient request or when they became symptomatic. All patients were 

followed-up for more than 144 months, or had died before that point. OS and DFS at 5, 10 and 12 

years was 68% and 90%, 34% and 74%, and 26% and 70%, respectively. 84 

31

Hormone therapy 

Immediate versus deferred hormonal treatment 

• Immediate versus deferred treatment for advanced prostate cancer was investigated by the MRC 

Prostate Working Party Investigators Group. An RCT of 943 men with asymptomatic metastases or 

locally advanced disease, not suitable for curative treatment, was undertaken, with randomisation 

to immediate or deferred hormone therapy. 85 

o There was a significant advantage in the immediate treatment group in terms of distant 

progression. Mortality was only significantly changed by treating immediately in those with 

M0 disease (Table 5). 

o A modest but statistically significant increase in OS was seen in the immediate treatment 

group, but not significant difference in prostate cancer mortality or symptom-free survival 

was demonstrated. 

o Due consideration must therefore be given to potential effects of long-term ADT versus the 

potential avoidance of such effects in patients if hormone therapy is deferred. 86 

Table 5: Effect of immediate versus deferred hormonal treatment 85 

Immediate Deferred 

Distant progression 26% 45% 

Mortality due to prostate cancer M0 disease 31.6% 48.8% 

M1 disease No significant No significant 

difference difference 

Hormone therapy plus standard care 

• The multicentre, international Early Prostate Cancer (EPC) study evaluated the efficacy and 

tolerability of adding the non-steroidal anti-androgen bicalutamide 150 mg once-daily to 

standard care (prostatectomy, radiotherapy or watchful waiting). 8113 patients with localised or 

locally advanced non-metastatic prostate cancer were included. 87 

o Objective PFS and OS were defined as the primary endpoints. At a third analysis, the median 

follow-up was 7.4 years. Exploratory analyses were also conducted to determine the efficacy 

of bicalutamide in clinically relevant subgroups. 

o A trend towards increased survival was seen for the subgroup treated with bicalutamide who 

would otherwise have undergone watchful waiting (HR 0.81; 95%CI: 0.66−1.01; p=0.06). 

o A significant improvement in objective PFS in favour of bicalutamide 150 mg for all locally 

advanced disease patients was demonstrated irrespective of standard care received (HR 

0.69; 95%CI: 0.58−0.83; p

Radiotherapy plus hormone therapy 

• A study by Widmark et al. has shown that the addition of radiotherapy to hormone therapy for 

men with locally advanced or high-risk prostate cancer halves the 10-year prostate cancer-specific 

mortality and substantially decreases overall mortality. 88 

o This phase III study comparing endocrine therapy with and without local radiotherapy 

randomised 875 patients with locally advanced prostate cancer (T3; 78%; PSA concentration 

EBRT +/− neoadjuvant, concomitant and adjuvant hormone therapy 

Radiotherapy alone 

• In locally advanced disease, EBRT alone has been shown to have a poorer outcome than in 

localised prostate cancer. Consequently, combination therapy with radiotherapy and hormone 

therapy is rapidly being accepted as standard practice. 

• Although it has been widely used, there are still many uncertainties associated with radical 

radiotherapy with regard to the optimum dose and field size (particularly to what extent the 

treatment volume should try to include pelvic lymph nodes). These uncertainties are compounded 

by the availability of new approaches to the delivery of radiotherapy, such as IMRT. The latter is 

intended to shape the radiation field more precisely to the tumour volume, thereby reducing the 

side-effects of treatment and possibly allowing dose escalation that enhances its local efficacy. 

Radiotherapy target volume/lymph nodes 

• In high-risk patients the consensus is that the seminal vesicles should be included. 

• The RTOG 9413 trial was designed to determine whether there was an advantage in terms 

of PFS with total androgen suppression, whole pelvic radiotherapy followed by a prostate 

boost compared with total androgen suppression and prostate-only radiotherapy. The trial 

also investigated the timing of hormone therapy with a further randomisation. One group 

received neoadjuvant hormone therapy followed by concurrent total androgen suppression and 

radiotherapy while the other group was treated with radiotherapy followed by adjuvant hormone 

therapy. Patients with non-metastatic disease but an estimated risk of lymph node involvement of 

>15% were randomised between the 4 arms. 89 

o The difference in OS for the 4 arms was statistically significant (p=0.027). 

o However, no statistically significant differences were found in PFS or OS between neoadjuvant 

versus adjuvant hormone therapy and whole pelvis radiotherapy compared with prostateonly 

radiotherapy. A trend towards a difference was found in PFS (p=0.065) in favour of the 

whole pelvic radiotherapy + neoadjuvant hormone arm compared with the prostate-only 

radiotherapy + neoadjuvant hormones and whole pelvic radiotherapy + adjuvant hormone 

treatment arms. 

o These results have demonstrated that when neoadjuvant hormone therapy is used in 

conjunction with radiotherapy, whole pelvic treatment yields a better PFS than prostate-only 

radiotherapy. It also showed an improved OS when whole pelvic radiotherapy was combined 

with neoadjuvant rather than short-term adjuvant hormone therapy. 

Radiotherapy dose escalation 

• Evidence suggests that patients treated with radiotherapy to the prostate have a significantly 

better outcome, because the dose to the gland is increased. The benefit is greatest in those 

patients with high-risk features. 

• Debate remains over the best way of increasing the dose without significantly increasing normal 

tissue toxicity. 3D-CRT, IMRT and high dose rate (HDR) brachytherapy boost are methods currently 

under evaluation. 

34

• Evidence of the benefits of dose escalation has been demonstrated for T1−T3 prostate cancer by 

Pollack in a phase III randomised study at the MD Anderson Hospital. 53 

o A total of 305 men were randomised between 1993 and 1998 to compare the efficacy of 

70 Gy versus 78 Gy with a median follow-up of 60 months. The primary endpoint was FFF, 

including biochemical failure, which was defined as three rises in PSA level. 

o The FFF rates for the 70 Gy and 78 Gy arms at 6 years were 64% and 70%, respectively 

(p=0.03). 

o Dose escalation to 78 Gy preferentially benefited those with a pre-treatment PSA 

concentration >10 ng/ml; the FFF rate was 62% for the 78 Gy arm versus 43% for those who 

received 70 Gy (p=0.01). For patients with a pre-treatment PSA concentration ≤10 ng/ml, no 

significant dose response was found, with an average 6-year FFF rate of about 75%. 

o Although no difference in OS was observed, the freedom from distant metastasis rate was 

higher for those with PSA concentrations >10 ng/ml who were treated to 78 Gy (98% versus 

88% at 6 years; p=0.056). 

• Dearnaley and colleagues have reported their findings from the MRC RT01 study. 54 

o In this 3D-CRT trial 843 men were randomised to standard dose of 64 Gy compared to an 

escalated dose of 74 Gy with all men receiving neoadjuvant hormone therapy. 

o Patients receiving the conventional dose had 5-year biochemical PFS rates of 60% compared 

with 71% in the dose-escalated arm. Advantages were also seen in terms of PFS and the 

decreased use of androgen suppression. 

o Although these and other studies have shown benefits from dose escalation with 3D-CRT 

techniques, this has been offset to a degree by a reported increase in late rectal toxicity. 

• Prospective non-randomised studies at the Memorial Sloan Kettering cancer centre have 

compared the outcomes of 1100 men who received doses in the range of 64 to 70 Gy and 76 to 

86 Gy using IMRT. The results were evaluated within prognostic risk groups (using clinical stage, 

Gleason grade and presenting PSA). 55 

• They demonstrated that increasing the dose delivered beyond 70.2 Gy in men with intermediate- 

and high-risk disease improved the 5-year actuarial PSA relapse-free survivals from 50% to 70% 

and 21% to 47%, respectively, in these two risk categories. 

• These results confirmed the advantage of dose escalated radiotherapy with doses of over 80 Gy. 

IMRT has the potential to reduce late rectal toxicity as shown in a further study by Zelefsky which 

reports 3-year actuarial ≥ grade 2 gastrointestinal toxicity at 4%. 56 

• A further development under investigation involves a change in the traditional fractionation 

schedules. Hypofractionation may improve cancer control for the same level of radiation-related 

toxicity and be a more effective treatment for prostate cancer with a predicted low alpha/ 

beta ratio. Phase II dose escalation studies using shortened schedules of hypofractionated IMRT 

regimens have indicated acceptable early toxicity. 57 

• The CHHiP study is currently recruiting patients in the UK to compare standard fractionation IMRT 

(74 Gy in 37 fractions) to two hypofractionated IMRT regimens (60 Gy in 20 fractions or 57 Gy in 

19 fractions) in combination with neoadjuvant hormone therapy. 58 

35

HDR brachytherapy boost 

• HDR brachytherapy is a safe, reproducible and effective way of boosting conventional EBRT. There 

is published evidence for this approach demonstrating improved biochemical control and causespecific 

survival without a significant increase in toxicity. 

• Currently, HDR brachytherapy is used in combination with EBRT and is felt appropriate for 

patients with high-risk localised or locally advanced prostate cancer. 90 

EBRT plus neoadjuvant hormone therapy 

• Neoadjuvant hormone therapy reduces prostate volume by 30−40%. 59, 60 This can reduce the size 

of the treatment field and as a result the level of toxicity experienced. 

• There are also reports of an additive or synergistic effect on tumour cell kill with combined 

therapy. Theories as to the mechanism of this include improved oxygenation by reducing tumour 

bulk and movement of hormone-responsive cells into a resting phase, which could reduce 

repopulation rate and enhance tumour cell death (increased apoptosis). 61 

• The RTOG 86-10 trial randomised 471 men with T2−T4 prostate cancer to radiotherapy +/− 4 

months of ADT (goserelin 3.6 mg depot once-monthly plus flutamide 250mg tid) before and 

during EBRT or to radiotherapy alone. The median follow-up was 6.7 years for all patients and 8.6 

years for surviving patients. 62 

o At median follow-up of 8.7 years for surviving patients, there was a trend to improved 

survival (8-year survival 53% versus 44%, p=0.1) for those treated by hormone therapy with 

radiotherapy, which was significant for the subgroup with Gleason grade 2−6 disease (70% 

versus 52%, p=0.015). 62 

o Ten-year OS estimates (43% versus 34%) and median survival times (8.7 versus 7.3 years) 

favoured combined therapy with hormones and radiation compared to radiation treatment 

alone; however, these differences did not reach statistical significance (p=0.12). 63 

o There was a statistically significant improvement in 10-year disease-specific mortality 

(23% versus 36%; p=0.01), distant metastases (35% versus 47%; p=0.006), DFS (11% versus 

3%; p


• Adjuvant androgen suppression immediately after radical radiotherapy has been shown to 

significantly increase OS, PFS, and significantly reduce local progression, distant metastases and 

biochemical progression in several large randomised studies. 

• Bolla et al. (EORTC 22863) randomised 415 patients with locally advanced non-metastatic prostate 

cancer (T1−4, Nx, M0) to receive either radiotherapy with immediate goserelin 3.6 mg therapy 

(every 4 weeks for 3 years) plus cyproterone acetate (CPA) during the first month of treatment for 

disease flare (n=207) or radiotherapy alone (n=208). 91 

o After a mean follow-up of 66 months, the 5-year DFS rate was 74% versus 40% for the 

combined and EBRT alone groups, respectively (p=0.001). 

o Furthermore, the corresponding OS and cancer-specific survival rates at 5 years were 78% and 

62% (p=0.0002), while the cancer-specific survival rates were 94% versus 79%. 

o A further analysis of this study with a median follow-up of 9.1 years reported 192 deaths 

(112 in radiotherapy alone and 80 in the combined treatment arm). 92 

o The addition of 3 years of ADT increased the 10-year OS from 39.8% to 58.1% (HR 0.60; 

95%CI: 0.45−0.80; p=0.0004), clinical PFS from 22.7% to 47.7% (HR 0.42; 95%CI: 0.33−0.55; 

p

• Hanks et al. (RTOG 92-02) investigated the use of long-term androgen suppression following 

neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced prostate cancer 

(T2c to T4 with no extra pelvic lymph node involvement and PSA

Locally Advanced (Non-metastatic) Disease: 

Relapse after Primary Treatment 

Figure 3: Treatment algorithm for locally advanced (non-metastatic) disease (cont.) 


Post-radical prostatectomy 


Failed local Rx with rising PSA 

and/or local recurrence+ Mo 

Active surveillance/watchful waiting Active surveillance/watchful waiting 

Hormone therapy alone Hormone therapy alone 


(EBRT) +/– concomitant +/– 

adjuvant hormone therapy 

Post-radical radiotherapy/ 

brachytherapy 

Salvage prostatectomy 

Novel local salvage therapy 




Rising PSA levels 

• The PSA concentration at which to define treatment failure after prostatectomy varies 

in the literature. 

Definitions of recurrence 

• The Phoenix definition of relapse after radiotherapy is nadir plus 2. 97 

• Patients whose PSA never falls to an undetectable level in the post-operative period are generally 

considered to have systemic disease. However, some may have local disease amenable to salvage 

radiotherapy, and so need to be assessed to determine the best management plan. 

• A PSA concentration that rises rapidly in the post-operative setting may be indicative of metastatic 

disease, while a PSA that remains undetectable over a long period then gradually rises may be 

more likely to indicate local recurrence. 

39

• Pound et al. carried out a retrospective review of 1997 men undergoing radical prostatectomy 

by a single surgeon for clinically localised disease with no neoadjuvant or adjuvant treatment. 98 

A PSA ≥0.2 ng/ml was deemed evidence of recurrence. 

o At 15 years, 15% had PSA elevation and 34% of these had developed metastases. 

o The median time from PSA elevation to metastatic disease was 8 years. 

o After development of metastases, the median actuarial time to death was 5 years. In the 

survival analysis, time to biochemical progression, Gleason grade and PSA doubling time 

were predictive of the probability and time to the development of metastatic disease. 

• After completion of radiotherapy and hormonal treatment, testosterone recovery usually occurs. 

This may cause some PSA elevation that is related to normal prostate tissue recovery and not 

disease recurrence. 

• The definition of disease recurrence in the setting of combined therapy remains a matter 

of debate and consensus is awaited. 

• Benign PSA rises (PSA bounce) occur in approximately 12% of patients following EBRT 

and 30% following LDR brachytherapy in the absence of neoadjuvant hormonal treatment 

(starting between 18 months and 2 years after treatment). 

Local recurrence after radical prostatectomy 

Overview 

• Overall, approximately 40% of patients who have a radical prostatectomy have biochemical 

evidence of recurrence at some point. 

• Determining whether relapse is local or distant is important in determining optimal treatment. 

However, post-prostatectomy imaging is unhelpful as this will always be negative, so there is 

no way of defining local versus distant disease categorically. Other factors that may aid this 

distinction include: 

o Timing and pattern of PSA relapse (rapid rise post-operatively indicates distant spread) 

o Involvement of seminal vesicles or lymph nodes 

o Margin status at surgery 

o Gleason grade 

• Radical salvage treatment is usually via radiotherapy to the prostate bed +/− hormone therapy. 

The optimal time of treatment, i.e. immediate adjuvant or early salvage EBRT, is currently 

uncertain. The timing and duration of hormone therapy is also unclear. 

• The RADICALS study is investigating the timing of radiotherapy (immediate versus early salvage) 

and hormone duration. 50 

40


• The EORTC 22911 study was designed to investigate benefit for immediate post-operative 

radiotherapy in 502 patients with pT3 disease or positive surgical margins as opposed to 

radiotherapy offered for biochemical or clinical relapse. 48 

o After a median follow-up of 5 years, biochemical PFS was significantly improved in the 

immediate radiotherapy group (74.0% versus 52.6%; p

Recurrence after radical radiotherapy 

Overview 

• The therapeutic options for recurrence following radiotherapy include: 

o Salvage radical prostatectomy: associated with 5-year biochemical DFS rates of 55−69%, but 

the technique is associated with a significant incidence of complications, such as rectal injury, 

anastamotic stricture and urinary incontinence. 

o Salvage cryotherapy: 5-year biochemical PFS ranges from 40% to 73%. The complications 

of salvage cryotherapy are erectile dysfunction, pelvic, rectal or perineal pain, recto-urethral 

fistula, bladder outlet obstruction and urethral stricture. 

o Salvage HIFU is currently under investigation. 

o Hormone therapy can be given in combination with local treatments or as monotherapy. 


• Touma et al. reviewed the efficacy and safety of salvage radical prostatectomy, cryotherapy and 

brachytherapy for recurrence following definitive radiotherapy. 100 

o Salvage radical prostatectomy is associated with 5-year biochemical DFS rates of 55−69%, but 

the technique is associated with a significant incidence of complications, such as rectal injury, 

anastomotic stricture and urinary incontinence. 

o The four studies of salvage cryotherapy reviewed used varying definitions of recurrence. 

The 5-year biochemical PFS ranged from 40% when failure was defined as PSA 2 above 

nadir, to 62% and 73% when failure was defined as PSA greater than 2 and greater than 4, 

respectively. 

o The complications of salvage cryotherapy are erectile dysfunction, pelvic, rectal or perineal 

pain, rectourethral fistula, bladder outlet obstruction and urethral stricture. 

• In one trial of 49 patients reported by Grado et al., complications included lower urinary tract 

symptoms, especially in the first 3 months. TURP was necessary in 14% of patients due to bladder 

outlet obstruction, while haematuria occurred in 4% of cases, stricture in 6%, rectal ulcers in 4% 

and rectal bleeding necessitating colostomy in 2%. 101 

• In 71 patients with localised disease following EBRT, following HIFU, 80% demonstrated negative 

biopsies and 61% had a nadir PSA concentration

Advanced Prostate Cancer (Metastatic): Management Options 

Figure 4: Treatment algorithm for advanced (metastatic) disease 






expectancy? 

• Symptoms: 

– Bowel? 






• Palliative care referral? 



• Pain control 

• Local radiotherapy 

Bone pain 

Spinal cord compression 

Nerve root compression 

• Continual assessment 

Second-/third-line if 

androgen sensitive? 




• PSA 

• Transrectal ultrasound (TRUS)/ 

biopsy (non mandatory if PSA 

>100 and radiological evidence 

of metastases) 

• Biochemistry screen 

• Full blood count 

• Bone scan 



Proven M1/M2 

First line hormone therapy 

Significant rise in PSA Clinical/ 

radiological progression 

Observation 

Second-/third-line hormone 

therapy 

Further progression 





















HRPC 

Based on MRC evidence, the majority of patients with metastatic disease should be treated. 

Deferred treatment is acceptable only in highly selected, informed patients. 

Clinical trials 

Chemotherapy 

Strontium 

Bisphosphonate 

43

Primary hormone therapy 

Overview 

• ADT is standard first-line treatment for the management of patients with metastatic disease. 

ADT can involve orchidectomy, LHRH agonists, anti-androgens and gonadotrophin-releasing 

hormone (GnRH) antagonists. 

• Orchidectomy remains the gold-standard ADT against which all other treatments are compared 

because of its rapid effects on total testosterone concentrations. 103 

104, 105 

• Survival appears equivalent with LHRH agonists and orchidectomy. 

• A meta-analysis has indicated that 2-year survival may be worse with medical treatment than 

with orchidectomy. 106 

• Patients, however, prefer medical treatment and in terms of usage, drug treatment represents 

the standard of care at all disease stages. 107−109 

• GnRH antagonists are clinically equivalent to LHRH agonists without causing the initial 

testosterone surge seen with LHRH agonists. Now licensed on the evidence of phase III clinical 

trial data, degarelix demonstrates reduced testosterone concentrations to below castrate levels 

in 3 days (90% decrease in median testosterone compared with leuprolide group experiencing 

a 65% increase in median testosterone levels; p

Table 6: Effect of immediate versus deferred hormonal treatment 85 

Combined (maximum) androgen blockade 

• There is debate over the use of combined androgen blockade (CAB). In 2000, the Prostate Cancer 

Trialists’ Collaborative Group published a meta-analysis of the available trials of CAB versus 

monotherapy. The analysis included 27 trials, which incorporated 8275 men, representing 98% 

111, 112 

of men ever randomised in trials of CAB versus monotherapy. 

o The 5-year survival for all patients receiving CAB was 25.4%, compared with 23.6% for 

patients receiving monotherapy. 

o In subgroup analyses, patients treated with CPA seemed to fare slightly worse than those 

treated with flutamide or nilutamide, mostly secondary to non-prostate cancer-related 

deaths. 

• If the CPA studies were excluded, the results were as follows: 111 

Immediate Deferred 

Distant progression 26% 45% 

Mortality due to prostate cancer M0 disease 31.6% 48.8% 

M1 disease No significant No significant 

difference difference 

o CAB with flutamide alone was associated with an 8% reduction in the risk of death (95%CI: 

0.86−0.98; p=0.02), which translates to a small but significant improvement in 5-year survival 

over castration alone. 

o CAB with flutamide plus nilutamide was associated with an 8% reduction in the risk of death 

(95%CI: 1.00−1.27; p=0.005), which translates to a small but significant improvement in 5-year 

survival of 2.9% over castration alone. 

o Conversely, CAB with CPA is associated with an increased risk of death of 13% (95%CI: 

1.00−1.27; p=0.04), which translates to a small but significant reduction in 5-year survival 

of 2.8% over castration alone. 

• It can be concluded that the choice of anti-androgen used for CAB has an impact on outcome, and 

that CAB with a non-steroidal anti-androgen may offer a small but significant survival benefit. 

45

Second- or third-line hormone therapy 

• Some patients will respond to second-line hormone therapy (CAB with the addition of an antiandrogen, 

anti-androgen withdrawal, diethylstilboestrol [DES]). Anti-androgen withdrawal 

responses are seen in approximately 25% of cases who have been treated with first-line CAB 

or have had substantial (>1 year response) to second-line CAB. 

• A common second-line treatment is the addition of an anti-androgen. A retrospective analysis 

of 122 patients who received the addition of bicalutamide 50 mg to goserelin for PSA and clinical 

progression showed a >50% decrease in PSA concentration in 30% of patients (responders) and 

a reduction in PSA concentration in 75% of all patients. The median duration of response from 

start of bicalutamide 50 mg was 291 days for responders and 193 days for the population as a 

whole. Those patients with a short duration of response to goserelin monotherapy (

Chemotherapy, Strontium and Bisphosphonates 

Those patients who do not respond to hormone therapy are considered to have hormone-refractory 

prostate cancer (HRPC; i.e. unresponsive to all hormone therapies) or castrate-refractory prostate 

cancer (unresponsive to treatment with LHRH agonists) and are candidates for chemotherapy, novel 

therapies and/or symptomatic local treatments. 

Chemotherapy 

• A prospective study by Tannock in 1996 compared the benefits of mitoxantrone 12 mg/m² every 

3 weeks plus prednisone 5 mg twice-daily with prednisone alone in 161 men with symptomatic 

HRPC. 116 

o The primary endpoint was palliative response defined as a 2-point decrease in pain as assessed 

by a 6-point pain scale. 

o There was a significant advantage to the chemotherapy combination with a 29% pain 

response compared to 12% with steroids alone. 

o The duration of palliation was 43 weeks versus 18 weeks (p

Side-effects 

• Side-effects of chemotherapy depend on the treatment, but usually include fatigue, nausea and 

vomiting, diarrhoea, hair loss and increased susceptibility to infection. Specific therapies to handle 

these side-effects may be necessary to improve the patient’s quality of life. 

Strontium 

• Metastatic pain can be palliated effectively with systemic radionuclide therapy with strontium 

chloride. 

• Relief of bone pain starts within 2 weeks. Possible initial bone pain flare may occur within 2 days, 

lasting 2−4 days. 

o Pain relief lasts 4−15 months. 

o 75−80% of patients experience significant palliation of pain. 

• A Canadian collaborative study showed significant improvement in quality of life, increased time 

to further metastases, significant reduction in the amount of additional radiotherapy needed, 

and significant falls in PSA and alkaline phosphatase. 120 

• Strontium is not associated with improvements in OS. 121 

• Four randomised clinical trials have reviewed the use of strontium. 122 

o One trial reported significant improvement in pain control, two trials reported fewer new 

sites of pain. 

o One trial showed no significant difference in pain control compared to a placebo but an 

improved 2-year survival rate. 

• A randomised clinical trial examining strontium versus placebo found a significant increase in 

median time to progression, but no significant effects on median OS or clinical response. 123 

Side-effects 

• The most notable side-effect of strontium is mild haematological suppression with a fall in 

circulating platelet and leukocyte counts recognised in most patients. 

o With usual therapeutic doses, platelets typically fall by 30% and leucocytes by 20%. 

o Clinically significant toxicity is rare, but its use is not recommended in patients with severely 

compromised bone marrow, platelet count

Bisphosphonates 

• The benefits of zoledronic acid, in combination with hormone therapy have been investigated 

in a study by Saad in men with HRPC and bone metastases. 124 This was a multicentre, randomised, 

placebo-controlled trial evaluating the efficacy of zoledronic acid 4 mg administered every 

3 weeks in 422 patients with HRPC for 15 months, with an option to continue for an additional 

9 months. 

o At the 2-year analysis, treatment with zoledronic acid was found to significantly reduce the 

percentage of patients with at least one skeletal-related event (SRE; defined as radiation for 

bone pain or to prevent pathological fracture/spinal cord compression; pathological fracture; 

spinal cord compression; surgery to bone; change in antineoplastic therapy) compared with 

placebo (38% versus 49%; p=0.028). All SREs were delayed. 

o Zoledronic acid also significantly delayed the time to first SRE by around 6 months (median 

488 versus 321 days; p=0.009). Furthermore, patients in the zoledronic acid group had 

consistently lower incidences of all types of SRE than the placebo group. Pain scores were 

consistently lower in patients taking zoledronic acid 4mg than placebo, and significantly 

at 3, 9, 18, 21 and 24 months (p


Overview 

• Radiotherapy has been a mainstay in the palliation of painful metastatic bone lesions. Palliative 

radiotherapy can also aid other complications of metastatic disease, such as compression of the 

spinal cord or a nerve root, haematuria, ureteric obstruction, perineal discomfort caused by the 

local progression of prostate cancer, and symptomatic metastatic lymphadenopathy. 


• Good evidence for the role of radiotherapy in palliation comes from McQuay et al. This systematic 

review covered 20 trials, which reported on 43 different radiotherapy fractionation schedules, and 

eight studies of radioisotopes. 128 

o Radiotherapy produced complete pain relief at 1 month in 395 out of 1580 (25%) patients, 

and at least 50% relief in 788 out of 1933 (41%) patients at some time during the trials. 

o In the largest trial, which included 759 patients, 52% achieved complete pain relief within 

4 weeks and the median duration of complete relief was 12 weeks. 

o The study found no difference between the use of radioisotopes (such as strontium) and 

EBRT for generalised disease, a finding supported by the work of Quilty et al. 

o In this latter study, 284 patients with prostate cancer and painful bone metastases were 

treated with local or hemi-body radiotherapy or strontium. Median survival was nonsignificantly 

different between groups (33 weeks with strontium versus 28 weeks with 

radiotherapy; p=0.1). 129 

o Both radiotherapy and strontium provided effective pain relief that was sustained for 

3 months in 63.6% of patients after hemi-body radiotherapy compared with 66.1% of 

patients after strontium, and in 61% of patients after local radiotherapy compared with 

65.9% of patients in the comparable strontium group. 

o Fewer patients reported new pain sites after strontium than after local or hemi-body 

radiotherapy (p


The MDT team should ensure regular communication with the primary care team. 

This may mean: 

• Timely provision of detailed discharge or outpatient summaries 

• Explanation of why a treatment route has been decided upon 

• The patient’s response to the chosen treatment 

• Sharing of protocols 

• Online educational resources 

• Agreement on prescribing policies 

• Provision of contact numbers for requests for information 

The local patient support network, e.g. partner/family, must be included in the information/education 

process through the use of: 

• Patient information materials 

• Audio visual materials such as videos, DVDs and Web-based information 

51

References 

1. Integrated Care Network. Integrated working: a guide. June, 2004. Available at: www. 

integratedcarenetwork.gov.uk/docs/publications/11/13.pdf. 

2. National Institute for Clinical Excellence. Guidance for commissioning cancer services. Improving 

outcomes in urological cancers. The research evidence. London: NICE, 2002. 

3. House of Commons Committee of Public Accounts. The NHS Cancer Plan: a progress report. 

Twentieth report of session 2005−06. London: The Stationery Office, 2006. 

4. Davison BJ, Parker PA, Goldenberg SL. Patients’ preferences for communicating a prostate cancer 

diagnosis and participating in medical decision-making. BJU Int 2004; 93: 47−51. 

5. Schroder FH, Hugosson Roobol MJ, et al. Screening and prostate cancer mortality in a randomized 

European study. N Engl J Med 2009; 360: 1320−1328. 

6. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Mortality results from a randomized prostate 

cancer screening trial. N Engl J Med 2009; 360: 1310−1319. 

7. Rosario DJ, Lane JA, Metcalfe C, et al. Contribution of a single repeat PSA test to prostate cáncer 

risk assessment: experience from the ProtecT study. Eur Urol 2008; 53: 777−784. 

8. Ben-Shlomo Y, Evans S, Ibrahim F, et al. The risk of prostate cancer amongst black men in the 

United Kingdom: the PROCESS cohort study. Eur Urol 2008; 53: 99−105. 

9. Steinberg GD, Carter BS, Beaty TH, Childs B, Walsh PC. Family history and the risk of prostate 

cancer. Prostate 1990; 17: 337−347. 

10. Negri E, Pelucchi C, Talamini R, et al. Family history of cancer and the risk of prostate cancer and 

benign prostatic hyperplasia. Int J Cancer 2005; 114: 648−652. 

11. Catalona WJ, Richie JP, DeKernion JB, et al. Comparison of prostate specific antigen concentration 

versus prostate specific antigen density in the early detection of prostate cancer: Receiver 

operating characteristic curves. J Urol 1994; 152 (6 Pt 1): 2031−2036. 

12. Elgamal A-AA, Cornillie FJ, Van Poppel HP, et al. Free-to-total prostate specific antigen ratio as a 

single test for detection of significant stage T1c prostate cancer. J Urol 1996; 156: 1042−1049. 

13. Aus G, Becker C, Lilja H, et al. Free-to-total prostate-specific antigen ratio as a predictor of nonorgan-confined 

prostate cancer (stage pT3). Scand J Urol Nephrol 2003; 37: 466−470. 

14. Aus G, Becker C, Franzen S, et al. Cumulative prostate cancer risk assessment with the aid of the 

free-to-total prostate specific antigen ratio. Eur Urol 2004; 45: 160−165. 

15. Hudson MA, Bahnson RR, Catalona WJ. Clinical use of prostate specific antigen in patients with 

prostate cancer. J Urol 1989; 142: 1011−1017. 

16. Brawer MK, Lange PH. Prostate-specific antigen in management of prostatic carcinoma. Urology 

1989; 33 (5 Suppl): 11−16. 

17. Partin AW, Carter HB, Chan DW, et al. Prostate specific antigen in the staging of localized prostate 

cancer: influence of tumor differentiation, tumor volume and benign hyperplasia. J Urol 1990; 

143: 747−752. 

18. Dearnaley DP, Kirby RS, Kirk D, Malone P, Simpson RJ, Williams G. Diagnosis and management of 

early prostate cancer. Report of a British Association of Urological Surgeons working party. BJU Int 

1999; 83: 18−33. 

19. DeAntoni EP, Crawford ED, Oesterling JE, et al. Age- and race-specific reference ranges for 

prostate-specific antigen from a large community-based study. Urology 1996; 48: 234−239. 

20. Xu ZQ, Hua LX, Qian LX, Wu HF. Effect of transrectal prostatic biopsy on serum prostate-specific 

antigen levels. Zhonghua Nan Ke Xue 2002; 8: 341−342. 

52

21. Tchetgen MB, Oesterling JE. The effect of prostatitis, urinary retention, ejaculation and 

ambulation on the serum prostate-specific antigen concentration. Urol Clin North Am 1997; 24: 

283−291. 

22. Gamé X, Vincendeau S, Palascak R, Milcent S, Fournier R, Houlgatte A. Total and free prostatespecific 

antigen levels during the first month of acute prostatitis. Eur Urol 2003; 43: 702−705. 

23. Catalona WJ, Partin AW, Slawin KM, et al. Use of the percentage of free prostate-specific antigen 

to enhance differentiation of prostate cancer from benign prostatic disease: A prospective 

multicenter clinical trial. JAMA 1998; 279: 1542−1547. 

24. Smith DS, Catalona WJ. Rate of change of serum PSA levels as a method for prostate cancer 

detection: J Urol 1994; 152: 1163−1167. 

25. Gustafsson O, Norming U, Almgard LE, et al. Diagnostic methods in the detection of prostate 

cancer: a study of a randomly selected population of 2,400 men. J Urol 1992; 148: 1827−1831. 

26. Mettlin C, Murphy GP, Babalan RJ, et al. The results of a five-year early prostate cancer detection 

intervention. Cancer 1996; 77: 150−159. 

27. Jones WT, Resnick MI. Prostate ultrasound in screening, diagnosis, and staging of prostate cancer. 

Prob Urol 1990; 4: 343−357. 

28. Ellis WJ, Chetner MP, Preston SD, Brawer MK. Diagnosis of prostatic carcinoma: The yield of serum 

prostate specific antigen, digital rectal examination and transrectal ultrasonography. J Urol 1994; 

152(5 I): 1520−1525. 

29. National Institute for Health and Clinical Excellence. Prostate cancer: diagnosis and treatment. Full 

guideline. London, NICE: 2008. 

30. Eskicorapci SY, Baydar DE, Akbal C, et al. An extended 10-core transrectal ultrasonography guided 

prostate biopsy protocol improves the detection of prostate cancer. Eur Urol 2004; 45: 444−448. 

31. Djavan B, Fong YK, Ravery V, et al. Are repeat biopsies required in men with PSA < or =4 ng/ml? A 

multiinstitutional prospective European study. Eur Urol 2005; 47: 38−44. 

32. Allen DJ, Hindley R, Clovis S, et al. Does body-coil magnetic-resonance imaging have a role in 

the preoperative staging of patients with clinically localized prostate cancer? BJU Int 2004; 94: 

534−538. 

33. Gerber G, Chodak GW. Assessment of value of routine bone scans in patients with newly 

diagnosed prostate cancer. Urology 1991; 37: 418−422. 

34. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, 

external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate 

cancer. JAMA 1998; 280: 969−974. 

35. van As NJ, Norman AR, Thomas K, et al. Predicting the probability of deferred radical treatment 

for localised prostate cancer managed by active surveillance. Eur Urol 2008; 54: 1297−1305. 

36. van den Bergh RC, Roemeling S, Roobol MJ, et al. Outcomes of men with screen-detected prostate 

cancer eligible for active surveillance who were managed expectantly. Eur Urol 2008; Sep 17 

[epub]. 

37. Draisma G, Boer R, Otto SJ, et al. Lead times and overdetection due to prostate-specific antigen 

screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J 

Natl Cancer Inst 2003; 95: 868−878. 

38. Selley S, Donovan J, Faulkner A, et al. Diagnosis, management and screening of early localised 

prostate cancer. Health Technol Assess 1997; 1: 1−96. 

53

39. Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early 

prostate cancer. N Engl J Med 2005; 352: 1977−1984. 

40. Singer PA, Tasch ES, Stocking C, et al. Sex or survival: trade-offs between quality and quantity of 

life. J Clin Oncol 1991; 9: 328−334. 

41. Bill-Axelson A, Holmberg L, Filen F, et al. Radical prostatectomy versus watchful waiting in 

localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial. J Natl 

Cancer Inst 2008; 100: 1144−1154. 

42. Bonney WW, Schned AR, Timberlake DS. Neoadjuvant androgen ablation for localised prostatic 

cancer. Pathology methods, surgical end points and meta-analysis of randomised trials. J Urol 

1999; 160: 1754−1760. 

43. Paul R, Van Randenborgh H, Kubler H, et al. Significance of neoadjuvant therapy before radical 

prostatectomy. Urologe A 2004; 43: 680−688. 

44. Selli C, Milesi C. Neoadjuvant androgen deprivation before radical prostatectomy. A review. 

Minerva Urol Nefrol 2004; 56: 165−171. 

45. Witjes WPJ, Schulman CC, Debruyne FMJ. Preliminary results of a prospective randomised study 

comparing radical prostatectomy versus radical prostatectomy associated with neo-adjuvant 

hormonal combination therapy in T2-3 N0 M0 prostatic carcinoma. Urology 1997; 49 (3 Suppl): 

65−69. 

46. Hachiya T, Minei S, Hirano D, et al. Adjuvant hormone therapy in patients with positive surgical 

margins after radical prostatectomy. Jpn J Urol 2002; 93: 469−475. 

47. Prayer-Galetti T, et al. Disease free survival in patients with pathological “C Stage” prostate cancer 

at radical prostatectomy submitted to adjuvant hormonal treatment. Eur Urol 2000; 38: 504, abs 

48. 

48. Bolla M, van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: a 

randomised controlled trial (EORTC trial 22911). Lancet 2005; 366: 572−578. 

49. Thompson Jr IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced 

prostate cancer: a randomized clinical trial. JAMA 2006; 296: 2329−2335. 

50. Parker C, Sydes MR, Catton C, et al. Radiotherapy and androgen deprivation in combination after 

local surgery (RADICALS): A new Medical Research Council/National Cancer Institute of Canada 

phase III trial of adjuvant treatment after radical prostatectomy. BJU Int 2007; 99: 1376−1379. 

51. Nilsson S, Norlen BJ, Widmark A. A systematic overview of radiation therapy effects in prostate 

cancer. Acta Oncol 2004; 43: 316−381. 

52. Dearnaley DP, Khoo VS, Norman AR, et al. Comparison of radiation side-effects of conformal and 

conventional radiotherapy in prostate cancer: a randomised trial. Lancet 1999; 353: 267−272. 

53. Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose response: results of the M. 

D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002; 53: 1097−1105. 

54. Dearnaley DP, Sydes MR, Graham JD, et al. Escalated-dose versus standard-dose conformal 

radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. 

Lancet Oncol 2007; 8: 475−487. 

55. Zelefsky MJ, Fuks Z, Lee HJ, et al. High dose radiation delivered by intensity modulated conformal 

radiotherapy improves the outcome of localized prostate cancer. J Urol 2001; 166: 876−878. 

56. Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose intensity modulated radiation therapy for prostate 

cancer: early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys 2002; 

52: 1111−1116. 

54

57. Amer AM, Mott J, Mackay RI, et al. Prediction of the benefits from dose-escalated 

hypofractionated intensity-modulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol 

Phys 2003; 56: 199−207. 

58. South CP, Khoo VS, Naismith O, Norman A, Dearnaley DP. A comparison of treatment planning 

techniques used in two randomised UK external beam radiotherapy trials for localised prostate 

cancer. Clin Oncol (R Coll Radiol) 2008; 20: 15−21. 

59. Shearer RJ, Davies JH, Gelister JS, Dearnaley DP. Hormonal cytoreduction and radiotherapy for 

carcinoma of the prostate. Br J Urol 1992; 69: 521−524. 

60. Forman JD, Kumar R, Haas G, et al. Neoadjuvant hormonal downsizing of localized carcinoma of 

the prostate: effects on the volume of normal tissue irradiation. Cancer Invest 1995; 13: 8−15. 

61. Hara I, Miyake H, Yamada Y. Neoadjuvant androgen withdrawal prior to external radiotherapy for 

locally advanced adenocarcinoma of the prostate. Int J Urol 2002; 9: 322−332. 

62. Pilepich MV, Winter K, John MJ, et al. Phase III RTOG trial 86-10 of androgen deprivation adjuvant 

to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol 

Phys 2001; 50: 1243−1252. 

63. Roach M 3rd, Bae K, Speight J, et al. Short-term neoadjuvant androgen deprivation therapy and 

external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. 

J Clin Oncol 2008; 26: 585−591. 

64. Denham JW, Steigler A, Wilcox C, et al. Time to biochemical failure and prostate-specific antigen 

doubling time as surrogates for prostate cancer-specific mortality: evidence from the TROG 96.01 

randomised controlled trial. Lancet Oncol 2008; 9: 1058−1068. 

65. D’Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. 6-month androgen 

suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized 

prostate cancer: a randomized controlled trial. JAMA 2004; 292: 821−827. 

66. National Institute for Health and Clinical Excellence. Low dose rate brachytherapy for localised 

prostate cancer. Interventional Procedure Guidance 132, July 2005. 

67. Crook J, Lukka H, Klotz L, et al. Systematic overview of the evidence for brachytherapy in clinically 

localised prostate cancer. CMAJ 2001; 164: 975−981. 

68. Merrick GS, Butler WM, Lief JH, Dorsey AT. Is brachytherapy comparable with radical 

prostatectomy and external beam radiotherapy for clinically localised prostate cancer? Tech Urol 

2001; 7: 12−19. 

69. Singh AM, Gagnon G, Collins B, et al. Combined external beam radiotherapy and Pd-103 

brachytherapy boost improves biochemical failure free survival in patients with clinically localized 

prostate cancer: results of a matched pair analysis. Prostate 2005; 62: 54−60. 

70. Potters L, Morgenstern C, Calugaru E, et al. 12-year outcomes following permanent prostate 

brachytherapy in patients with clinically localized prostate cancer. J Urol 2005; 173: 1562−1566. 

71. Wills F, Hailey D. Brachytherapy for prostate cancer. Alberta Heritage Foundation for Medical 

Research, Alberta Canada. 1999, Dec. (http://www.ahfmr.ab.ca/publications). 

72. Beyer DC, Priestley JB Jr. Biochemical disease-free survival following 125I prostate implantation. 

Int J Radiat Oncol Biol Phys 1997; 37: 559−563. 

73. Blasko JC, Wallner K, Grimm PD, Ragde H. Prostate specific antigen based disease control 

following ultrasound guided 125iodine implantation for stage T1/T2 prostatic carcinoma. J Urol 

1995; 154: 1096−1099. 

74. Wallner K, Roy J, Zelefsky M, Harrison L. Short-term freedom from disease progression after I-125 

prostate implantation. Int J Radiat Oncol Biol Phys 1994; 30: 405−409. 

55

75. Stock RG, Stone NN, DeWyngaert JK, Lavagnini P, Unger PD. Prostate specific antigen findings and 

biopsy results following interactive ultrasound guided transperineal brachytherapy for early stage 

prostate carcinoma. Cancer 1996; 77: 2386−2392. 

76. Beyer DC, Brachman DG. Failure free survival following brachytherapy alone for prostate cancer: 

comparison with external beam radiotherapy. Radiother Oncol 2000; 57: 263−267. 

77. Ragde H, Korb LJ, Elgamal A-A, et al. Modern prostate brachytherapy. PSA results in 219 patients 

with up to 12 years of observational follow up. Cancer 2000; 89: 135−141. 

78. Kupelian PA, Potters L, Khuntia D, et al. Radical prostatectomy, external beam radiotherapy or =72 Gy, permanent seed implantation, or combined seeds/ 

external beam radiotherapy for stage T1-T2 prostate cancer. Int J Radiat Oncol Biol Phys 2004; 58: 

25−33. 

79. Han KR, Cohen JK, Miller RJ, et al. Treatment of organ confined prostate cancer with third 

generation cryosurgery: preliminary multicenter experience. J Urol 2003; 170 (4 Pt 1): 1126−1130. 

80. Zisman A, Pantuck AJ, Cohen JK, Belldegrun AS. Prostate cryoablation using direct transperineal 

placement of ultrathin probes through a 17-gauge brachytherapy template-technique and 

preliminary results. Urology 2001; 58: 988−993. 

81. Parker MC, Cook A, Riddle PR, et al. Is delayed treatment justified in carcinoma of the prostate? Br 

J Urol 1985; 57: 724−728. 

82. Rana A, Chisholm GD, Khan M, et al. Conservative management with symptomatic treatment 

and delayed hormonal manipulation is justified in men with locally advanced carcinoma of the 

prostate. Br J Urol 1994; 74: 637−641. 

83. Wilt T, Nair B, MacDonald R, Rutks I. Early versus deferred androgen suppression in the treatment 

of advanced prostatic cancer. Cochrane Database Syst Rev 2001; CD003506. 

84. Adolfsson J, Steineck G, Hedlund PO. Deferred treatment of locally advanced nonmetastatic 

prostate cancer: a long-term followup. J Urol 1999; 161: 505−508. 

85. MRC Prostate Working Party Investigators Group. Immediate versus deferred treatment for 

advanced prostate cancer. Initial results of the MRC trial. Br J Urol 1997; 79: 235−246. 

86. Studer UE, Whelan P, Albrecht W, et al. Immediate or deferred androgen deprivation for patients 

with prostate cancer not suitable for local treatment with curative intent: European Organisation 

for Research and Treatment of Cancer (EORTC) Trial 30891. J Clin Oncol 2006; 24: 1868−1876. 

87. McLeod DG, Iversen P, See WA, et al. Bicalutamide 150 mg plus standard care versus standard care 

alone for early prostate cancer. BJU Int 2006; 97: 247−254. 

88. Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in 

locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet 2009; 

373: 301−308. 

89. Lawton CA, DeSilvio M, Roach M 3rd, et al. An update of the phase III trial comparing whole pelvic 

to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated 

analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions. Int J Radiat 

Oncol Biol Phys 2007; 69: 646−655. 

90. Martinez AA, Gustafson G, Gonzalez J, et al. Dose escalation using conformal high dose rate 

brachytherapy improves outcome in unfavorable prostate cancer. Int J Radiat Oncol Biol Phys 

2002; 53: 316−327. 

91. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and 

external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III 

randomised trial. Lancet 2002; 360: 103−106. 

56

92. Bolla M, Collette L, Van Tienhoven G, et al. Ten year results of long term adjuvant androgen 

deprivation with goserelin in patients with locally advanced prostate cancer treated with 

radiotherapy: A phase III EORTC study. Int J Radiat Oncol Biol Phys 2008; 72 (1 Suppl1): S30−S31. 

93. Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment 

of prostate cancer. N Engl J Med 2009; 360: 2516−2527. 

94. Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive 

radiotherapy in prostate carcinoma − long-term results of phase III RTOG 85-31. Int J Radiat Oncol 

Biol Phys 2005; 61: 1285−1290. 

95. Hanks GE, Pajak TF, Porter A, et al. Phase III trial of long-term adjuvant androgen deprivation 

after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the 

prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol 2003; 21: 3972−3978. 

96. Horwitz EM, Bae K, Hanks GE, et al. Ten-year follow-up of radiation therapy oncology group 

protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally 

advanced prostate cancer. J Clin Oncol 2008; 26: 2497−2504. 

97. Roach M, Hanks G, Thames H, et al. Defining biochemical failure following radiotherapy with or 

without hormonal therapy in men with clinically localized prostate cancer: recommendations of 

the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006; 65: 965−974. 

98. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation 

following radical prostatectomy. JAMA 1999; 281: 1591−1597. 

99. Messing EM, Manola J, Yao J, et al. Immediate versus deferred androgen deprivation 

treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic 

lymphadenectomy. Lancet Oncol 2006; 7: 472−479. 

100. Touma NJ, Izawa JI, Chin JL. Current status of local salvage therapies following radiation failure 

for prostate cancer. J Urol 2005; 173: 373−379. 

101. Grado GL, Collins JM, Kriegshauser, JS et al. Salvage brachytherapy for localized prostate cancer 

after radiotherapy failure. Urology 1999; 53: 2−10. 

102. Gelet A, Chapelon JY, Poissonier L, et al. Local recurrence of prostate cancer after external beam 

radiotherapy: early experience of salvage therapy using high-intensity focused ultrasonography. 

Urology 2004; 63: 625−629. 

103. Tombal B. The importance of testosterone control in prostate cancer. Eur Urol Suppl 2007; 6: 

834−839. 

104. Vogelzang NJ, Chodak GW, Soloway MS, et al. Goserelin versus orchiectomy in the treatment 

of advanced prostate cancer: final results of a randomized trial. Zoladex Prostate Study Group. 

Urology 1995; 46: 220−226. 

105. Kaisary AV, Tyrrell CJ, Peeling WB, Griffiths K. Comparison of LHRH analogue (Zoladex) with 

orchiectomy in patients with metastatic prostatic carcinoma. Br J Urol 1991; 67: 502−508. 

106. Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-therapy androgen suppression in men with 

advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 2000; 132: 

566−577. 

107. Shahinian VB, Kuo YF, Freeman JL, Orihuela E, Goodwin JS. Increasing use of gonadotropinreleasing 

hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005; 103: 

1615−2164. 

108. Kaku H, Saika T, Tsushima T, et al. Time course of serum testosterone and luteinizing hormone 

levels after cessation of long-term luteinizing hormone-releasing hormone agonist treatment in 

patients with prostate cancer. Prostate 2006; 66: 439−444. 

57

109. Cassileth BR, Soloway MS, Vogelzang NJ, et al. Quality of life and psychosocial status in stage D 

prostate cancer. Zoladex Prostate Cancer Study Group. Qual Life Res 1992; 1: 323−330. 

110. Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month 

comparative, randomized, open-label, parallel-group phase III study in patients with prostate 

cancer. BJU Int 2008; 102: 1531−1538. 

111. Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate 

cancer: an overview of the randomised trials. Lancet 2000; 355: 1491−1498. 

112. Klotz L. Combined androgen blockade in prostate cancer: Meta-analyses and associated issues. 

BJU Int 2001; 87: 806−813. 

113. Sartor AO, Tangen CM, Hussain MH, et al. Antiandrogen withdrawal in castrate-refractory 

prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer 2008; 112: 2393−2400. 

114. Byar DP. Treatment of prostatic cancer: studies by the Veterans Administration Cooperative 

Urological Research Group. Bull N Y Acad Med 1972; 48: 751−766. 

115. Robinson MR, Smith PH, Richards B, et al. The final analysis of the EORTC Genito-Urinary Tract 

Cancer Co-Operative Group phase III clinical trial (protocol 30805) comparing orchidectomy, 

orchidectomy plus cyproterone acetate and low dose stilboestrol in the management of 

metastatic carcinoma of the prostate. Eur Urol 1995; 28: 273−283. 

116. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or 

prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized 

trial with palliative end points. J Clin Oncol 1996; 14: 1756−1764. 

117. Small EJ, Halabi S, Dawson NA, et al. Antiandrogen withdrawal alone or in combination with 

ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). 

J Clin Oncol 2004; 22: 1025−1033. 

118. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone 

for advanced prostate cancer. N Engl J Med 2004; 351: 1502−1512. 

119. Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock I. Docetaxel plus prednisone 

or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 

study. J Clin Oncol 2008; 26: 242−245. 

120. Porter AT, McEwan AJ, Powe JE, et al. Results of a randomised phase III trial to evaluate the 

efficacy of strontium-89 adjuvant to local field EB-RT in the management of endocrine resistant 

metastatic prostate cancer. Int J Radiat Oncol Biol Phys 1993; 25: 805−813. 

121. Brundage MD, Crook JM, Lukka H, et al. Use of strontium-89 in endocrine refractory prostate 

cancer metastatic to bone. Provincial genitourinary cancer disease group. Cancer Prev Control 

1998; 2: 79−87. 

122. Robinson RG, Preston DF, Schiefelbein M, Baxter KG. Strontium–89 therapy for the palliation of 

pain due to osseous metastases. JAMA 1995; 274: 420−424. 

123. Tu SM, Millikan RE, Mengistu B, et al. bone targeted therapy for advanced and androgen 

independent prostate cancer. A randomised phase II trial. Lancet 2001; 357: 336−341. 

124. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid 

in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94: 

1458−1468. 

125. Dearnaley DP, Mason MD, Parmar MK, Sanders K, Sydes MR. Adjuvant therapy with oral sodium 

clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results 

from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol 2009; 10: 872−876. 

58

126. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced exposed bone 

(osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention and treatment. 

J Oral Maxillofac Surg 2005; 63: 1567−1575. 

127. Zometa (zoledronic acid). Summary of product characteristics, July 2008. 

128. McQuay HJ, Carroll D, Moore RA. Radiotherapy for painful bone metastases. A systematic review. 

Clin Oncol 1997; 9: 150−154. 

129. Quilty PM, Kirk D, Bolger JJ, et al. A comparison of the palliative effects of strontium-89 and 

external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 1994; 31: 33−40. 

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MDT (multi-disciplinary team) guidance for managing prostate cancer

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